Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial

Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury

“…The findings suggest that in addition to the important role of hydrophobicity, there may be a therapeutically addressable threshold for hepatic BA-induced injury by targeting the return of BAs to the liver by inhibiting the function of the intestinal bile acid transporter. Further studies will be required to determine if similar mechanisms are responsible in part for the clinical benefit of IBAT inhibitors that was recently demonstrated in children with progressive familial intrahepatic cholestasis and Alagille syndrome ( 21 , 22 ).…”

“…In the Mdr2 KO ( Abcb4 KO) model of cholestatic liver injury and sclerosing cholangitis, pharmacological inhibition of the ileal BA transporter (IBAT/ASBT; Slc10a2 ) increases fecal BA elimination, leading to reductions in liver BA concentrations and improvement in biomarkers of hepatocellular and cholestatic damage ( 8 , 19 ). IBAT inhibitors are being evaluated in clinical trials as an anticholestatic therapy ( 20 ) and have demonstrated clinical benefit in children and been approved for the treatment of progressive familial intrahepatic cholestasis and Alagille syndrome ( 21 , 22 ). In the following study, we tested whether blocking IBAT-mediated return of BAs to the liver in the enterohepatic circulation would be protective in Cyp2c70 KO mice and investigated the predicted cytotoxicity of the humanized BA pool composition in this model.…”

Development of the Patient- and Observer-Reported PRUCISION Instruments to Assess Pruritus and Sleep Disturbance in Pediatric Patients with Cholestatic Liver Diseases

“…Quantitative measurement characteristics, including an empirically derived threshold for clinically meaningful change in pruritus score, were established based on an independent, blinded, psychometric analysis that is the subject of a companion article in this issue. In brief, the psychometric performance of the ObsRO PRUCISION instrument was evaluated using data from the phase 3, randomized, placebo-controlled study of odevixibat in patients with PFIC (NCT03566238) [ 37 ]. Scores on the PRUCISION scale in this patient population were compared with scores from other established rating scales (i.e., patient-, caregiver-, and clinician-reported Global Impression of Change and Global Impression of Symptoms scales; Pediatric Quality of Life Inventory and family impact module) to test the instrument’s reliability, construct validity, and sensitivity to change.…”

Validation of the PRUCISION Instruments in Pediatric Patients with Progressive Familial Intrahepatic Cholestasis

“…The psychometric measurement properties (i.e., reliability, construct validity, sensitivity to change) of the PRO/ObsRO instruments were examined through analysis of data from the randomized, double-blind, placebo-controlled PEDFIC 1 study [ 11 ] (for a study flowchart, see Fig. 2 ).…”

“…The PEDFIC 1 study consisted of a screening period with a duration of 5–8 weeks, a 24-week treatment period, and a 4-week follow-up period. The PEDFIC 1 study materials received central or local ethics committee (CEC and LEC, respectively) approval from all 45 study sites in the United States, Canada, Europe, Australia, and the Middle East that intended to enroll patients (i.e., from 10 CECs representing 21 sites and from 22 LECs representing 24 sites); the full list of ethics committees providing approval is available in the appendix of the PEDFIC 1 article [ 11 ]. In addition, the study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines; all patients or their caregivers provided written consent prior to study participation.…”